Groups are stratified by day 1 status: no diuretics vs diuretic therapy
with response. To convert milligrams per deciliter to micromoles per liter,
multiply by 88.4. To convert milligrams per deciliter to millimoles per liter,
multiply by 0.357.

Figure 2. Time to Death or Dialysis From Day
of Consultation in Intensive Care Unit

Groups are stratified by day 1 status. For those patients who were
diuretic resistant (furosemide equivalent per milliliter ratio ≥1.0), the
No. at risk for days 1, 2, 3, and 5 were 35, 19, 10, and 3, respectively.
Analysis includes 411 of the 416 patients who survived at least 7 days after
nephrology consultation in the intensive care unit. Data are excluded for
5 patients who died at an unknown time.

Table 1. Baseline Patient Characteristics
on First Day of Nephrology Consultation*

Author Affiliations: Division of Nephrology, University of California, San Diego, Medical Center (Dr Mehta and Mss Pascual and Soroko); and Divisions of Nephrology, Moffitt-Long Hospitals and UCSF–Mt Zion Medical Center, University of California, San Francisco (Dr Chertow).

Context Acute renal failure is associated with high mortality and morbidity.
Diuretic agents continue to be used in this setting despite a lack of evidence
supporting their benefit.

Objective To determine whether the use of diuretics is associated with adverse
or favorable outcomes in critically ill patients with acute renal failure.

Design Cohort study conducted from October 1989 to September 1995.

Patients and Setting A total of 552 patients with acute renal failure in intensive care units
at 4 academic medical centers affiliated with the University of California.
Patients were categorized by the use of diuretics on the day of nephrology
consultation and, in companion analyses, by diuretic use at any time during
the first week following consultation.

Main Outcome Measures All-cause hospital mortality, nonrecovery of renal function, and the
combined outcome of death or nonrecovery.

Results Diuretics were used in 326 patients (59%) at the time of nephrology
consultation. Patients treated with diuretics on or before the day of consultation
were older and more likely to have a history of congestive heart failure,
nephrotoxic (rather than ischemic or multifactorial) origin of acute renal
failure, acute respiratory failure, and lower serum urea nitrogen concentrations.
With adjustment for relevant covariates and propensity scores, diuretic use
was associated with a significant increase in the risk of death or nonrecovery
of renal function (odds ratio, 1.77; 95% confidence interval, 1.14-2.76).
The risk was magnified (odds ratio, 3.12; 95% confidence interval, 1.73-5.62)
when patients who died within the first week following consultation were excluded.
The increased risk was borne largely by patients who were relatively unresponsive
to diuretics.

Conclusions The use of diuretics in critically ill patients with acute renal failure
was associated with an increased risk of death and nonrecovery of renal function.
Although observational data prohibit causal inference, it is unlikely that
diuretics afford any material benefit in this clinical setting. In the absence
of compelling contradictory data from a randomized, blinded clinical trial,
the widespread use of diuretics in critically ill patients with acute renal
failure should be discouraged.

Acute renal failure (ARF) in hospitalized patients may be associated
with low, normal, or excess extracellular volume, depending on the cause of
the ARF, accompanying conditions (eg, heart failure, liver disease), and patterns
of administration of crystalloids and colloids. Diuretic agents are frequently
given to augment renal salt and water excretion in the setting of extracellular
volume overload.

Diuretics are also frequently given during ARF in an effort to "convert"
oliguric to nonoliguric ARF, since oliguria has been recognized as a proxy
for the severity of ARF and the likelihood of requiring dialysis.1- 4 Despite
the ubiquity of this practice, there is scant evidence that diuretics provide
any material benefit to patients with ARF. Indeed, the "conversion" of oliguric
to nonoliguric ARF may reflect the severity of disease (diuretic-responsive
ARF) rather than a valid (and favorable) response to therapy.5- 7 Moreover,
the use of diuretics may increase the risk of ARF when given before radiocontrast
exposure8- 10 and
in other clinical settings,11- 13 raising
the possibility that diuretics may be harmful in patients with established
ARF. Several randomized clinical trials have explored the use of diuretics
in established ARF and have not shown benefit in survival or recovery of renal
function, although all studies were hampered by low statistical power.14- 17

We hypothesized that the use of diuretics during ARF would be associated
with an increase in mortality, hospital length of stay, and nonrecovery of
renal function in critically ill patients with ARF due to either direct effects
or indirect effects of delaying dialytic support. To explore these questions,
we examined data from a cohort of critically ill patients with ARF. Recognizing
the limitations of comparing therapies that have not been randomly assigned,
we attempted to adjust for confounding and practice variation with regression
methods complemented by propensity scores.

METHODS

Study Cohort

Data were collected on all intensive care unit (ICU) patients with ARF
who received nephrology consultation at 4 teaching hospitals (University of
California San Diego Medical Center, San Diego Veterans Affairs Medical Center,
San Diego Naval Hospital, and University of California, Irvine, Medical Center)
from October 1989 to September 1995. Acute renal failure was defined using
standard laboratory parameters. For patients with no history of kidney disease
or known laboratory values, ARF was defined either by a blood urea nitrogen
(BUN) level of 40 mg/dL or higher (≥14.3 mmol/L) or a serum creatinine
level of 2.0 mg/dL or higher (≥177 µmol/L). For others, ARF was defined
by a sustained rise in serum creatinine levels of 1 mg/dL or more (≥88.4
µmol/L) compared with baseline. Exclusion criteria included previous
dialysis, kidney transplantation, urinary tract obstruction, and hypovolemia.
Informed consent was obtained from all study participants or their next-of-kin.

Patients were followed up prospectively from the time of initial nephrology
service consultation through hospital discharge. A total of 851 ARF cases
were initially evaluated. No information on vital status was available in
31 patients (4%). Of the 820 remaining, data sufficient to calculate generic
and disease-specific severity of illness scores for risk adjustment were available
in 605 patients (74%). Information on the use of diuretics from the initial
ICU consultation day onward was available in 552 patients (91%), who comprised
the analytic sample.

The primary outcome measure was all-cause hospital mortality. We also
considered the combined end point of either mortality or nonrecovery of renal
function and lengths of ICU and hospital stay. Recovery of renal function
was defined as being dialysis independent with a serum creatinine level of
2.0 mg/dL or less (≤177 µmol/L) or no more than 20% higher than baseline
at the time of hospital discharge. The origin of ARF was classified as follows:
ischemic acute tubular necrosis, nephrotoxic acute tubular necrosis, multisystem
disorder, or uncertain.

Baseline vital signs, hemodynamic data (where available), and laboratory
data were recorded for the first ICU day and each day from the time of nephrology
consultation. Renal function was assessed daily from records of urine output,
BUN level, and serum creatinine level. Generic and disease-specific severity-of-illness
scores were computed on each successive ICU day. We determined the number
of organ systems in failure based on a modification of the criteria of Chang
et al.18 We used published criteria for each
organ system failure.19 We categorized patients
as taking or not taking diuretics on each of the first 7 days following consultation
and "ever" or "never" using diuretics during this week. Additionally, we categorized
patients treated with 1 vs 2 or more diuretic agents and identified specific
medications and daily doses for secondary analyses. Oliguria was defined as
urine output of less than 400 mL/d. To estimate the response to diuretics,
we calculated the total daily dose of loop diuretic (in furosemide equivalents)
divided by the total urine output in milliliters. For this calculation, 1
mg of bumetanide was considered to be equivalent to 40 mg of furosemide.

Statistical Analysis

Continuous variables were expressed as mean (SD) (or 10% and 90% confidence
limits) or median and compared with the t test or
the Wilcoxon rank sum test where appropriate. Categorical variables were expressed
as proportions and compared with the Mantel-Haenszel χ2 test.
Variables with significant associations on univariate screening were considered
candidates for multivariable analysis, along with age, sex, and race. Multivariable
logistic regression was performed using backward variable selection, with
variable exit criteria set at P<.05. Variables
not selected by the automated procedure were added back into models individually
to evaluate for residual confounding. The area under the receiver operating
characteristic curve was used to assess model discrimination.20 Calibration
was estimated using the Hosmer-Lemeshow goodness-of-fit test.21

In addition to adjusting for significant covariates in multivariable
regression, residual confounding and selection effects were addressed using
propensity scores.22 To develop the propensity
score, we included in a separate multivariable logistic regression analysis
all factors that differed among the diuretic and no diuretic groups, using
a more liberal significance criterion of P<.25.
With diuretic use as the dependent variable, we fit a model predicting the
likelihood or "propensity" of diuretic use. We then incorporated the propensity
score as a covariate in a logistic regression model using mortality as the
dependent variable. Inclusion of the propensity score as a covariate in a
multivariable regression theoretically normalizes the likelihood of treatment
(in this case, diuretics) and may effectively adjust for unobserved confounding
and selection bias, thereby refining regression estimates. We performed these
analyses again using the combined end point of mortality or nonrecovery of
renal function. Although the primary analysis incorporated data from the day
of consultation, we conducted companion analyses for other time points. Finally,
we used the Kaplan-Meier product limit method23 to
calculate the time to death or the provision of dialysis for ARF (censored
at day 60) and compared survival curves with the log-rank test. P≤.05 (2-tailed) was considered statistically significant. All analyses
were conducted using SAS statistical software, version 8 (SAS Institute Inc,
Cary, NC).

RESULTS

Factors Associated With Diuretic Use

Characteristics for the diuretic and no diuretic groups on the day of
nephrology consultation are shown in Table
1. Few data were missing, except for the invasive physiologic variables,
which were individually available in 40% to 76% of patients. The mean age
was significantly higher and BUN and creatinine levels significantly lower
among diuretic-treated patients on day 1 of ICU consultation. There were no
significant differences in APACHE II (Acute Physiology and Chronic Health
Evaluation II) or APACHE III scores. Among patients who underwent invasive
hemodynamic monitoring, those with higher pulmonary capillary wedge pressure
and lower cardiac index were more likely to be given diuretics. The proportion
of patients given diuretics overall declined from 59% to 44% to 40% during
the first 3 days following consultation, although an increasing fraction of
those taking diuretics were nonoliguric (59% to 80% to 86%). Although there
were initially no differences in severity-of-illness scores, mean APACHE III
scores were lower in diuretic-treated patients on day 2 (91.9 vs 87.3, P = .08) and day 3 (92.8 vs 82.7, P<.001).
Sixty-six (29%) of the 226 patients not taking diuretics at the time of consultation
were given diuretics during the following week.

The propensity score itself can be interpreted as the likelihood of
being given diuretics based on the observed array of covariates included in
the model. The mean propensity score was 0.59 (ie, the fraction of patients
given diuretics on day 1); the range was 0.225 × 10−6to
0.910.

Mortality and Nonrecovery of Renal Function and Diuretic Use

Two hundred ninety-four (53%) of 552 patients died in-hospital. Fifty-six
(19%) of 294 patients who died recovered renal function before death. Among
the 258 patients who survived (47%), 17 (7%) were dialysis dependent after
discharge. We therefore fit distinct logistic regression models for in-hospital
mortality, nonrecovery of renal function, and the combined outcome of mortality
or nonrecovery of renal function (Table
2). In the covariate-adjusted models, we included age, sex, and
the first consultation day values for heart rate, BUN, creatinine, log urine
output, and respiratory, hematologic, and liver failure based on previous
analyses.24 Diuretic use was associated with
a 68% (95% confidence interval [CI], 6%-164%) increase in in-hospital mortality
and a 77% (95% CI, 14%-176%) increase in the odds of death or nonrecovery
of renal function. In these models, there were no significant interactions
between diuretic use and urine output. Neither a history of congestive heart
failure nor the presence of cardiac organ system failure explained the increased
risks observed.

There was no difference in hospital length of stay by use of diuretics
on the first day of consultation (median, 21.5 vs 22.5 days; P = .95). However, subsequent diuretic use was associated with significantly
longer lengths of stay (median difference, 4-10 days; all comparisons were
at least P<.01 for each of consultation days 2-7).
The median time from consultation to first dialysis was also significantly
prolonged among patients given diuretics (median difference, 1-2 days; P<.01 for each of consultation days 1-7).

Since many patients crossover as users and nonusers of diuretics, we
also compared results of patients classified as "ever" vs "never" users of
diuretics, excluding individuals who died within the first week following
consultation. In these analyses (n = 416), the odds ratio (OR) of death or
nonrecovery of renal function in "ever" users of diuretics was 2.01 (95% CI,
1.26-3.20). These results remained statistically significant after covariate
(OR, 3.15; 95% CI, 1.74-5.70) and covariate and day 1 propensity score adjustment
(OR, 3.12; 95% CI, 1.73-5.62). As with the primary analyses, these models
exhibited good discrimination and were well calibrated.

Single vs Combination Diuretic Use, Specific Diuretic Use, and Dosage

Several diuretic agents and diuretic combinations were used. Of the
326 patients given diuretics on ICU consultation day 1, 203 (62%) were given
furosemide, 189 (58%) were given bumetanide, 106 (33%) were given metolazone,
and 13 (4%) were given hydrodiuril. Loop and thiazide diuretics in combination
were given to 105 patients (32%). The median (with 10%-90% range) doses of
furosemide, bumetanide, and metolazone were 80 (20-320), 10 (2-29), and 10
(5-20) mg/d, respectively. Although diuretic use was associated with mortality,
nonrecovery of renal function, and prolonged time to initiation of dialysis,
there were no significant differences among patients taking single vs combination
diuretics for any of these parameters.

Index of Diuretic Responsiveness

Since higher doses of diuretics are often used in patients who are oliguric
or have declining urine output, we calculated the furosemide dose equivalent
per milliliter per day of urine output as an index of the degree of diuretic
responsiveness and, potentially, the severity of renal injury. The median
dose equivalent per milliliter ratio was 0.34 mg/mL (10%-90% range, 0.02-4.22).
Expressed in clinical terms, the 10% to 90% ratio ranged from very responsive
(1000 mL associated with a single 20-mg dose of furosemide) to very unresponsive
(114 mL associated with 240 mg of furosemide given twice daily). We a priori
selected a ratio of 1.0 to stratify analyses by diuretic responsiveness. Patients
with a dose equivalent per milliliter ratio of 1.0 or higher on the day of
consultation had a higher odds of death or nonrecovery compared with nonusers
of diuretics (OR, 2.94; 95% CI, 1.61-5.36). In contrast, patients with a dose
equivalent per milliliter ratio of less than 1.0 experienced no significant
increase in risk (OR, 1.15; 95% CI, 0.79-1.68). Results were similar when
analyses were stratified by a dose equivalent per milliliter ratio of 0.5
(OR, 2.75; 95% CI, 1.66-4.54; and OR, 0.97; 95% CI, 0.65-1.45; for dose equivalent
per milliliter ratios of ≥0.5 and <0.5, respectively). In other words,
the increase in risk was borne largely by patients who were relatively unresponsive
to diuretics. Moreover, the risk associated with a high dose equivalent per
milliliter ratio was magnified over time (day 2 following consultation: OR,
3.61; 95% CI, 1.58-8.21; day 3 following consultation: OR, 7.12; 95% CI, 1.67-30.27).

Figure 1 shows the relative
differences in mean creatinine levels, mean BUN levels, and median urine output
for patients stratified by diuretic use and the dose equivalent per milliliter
ratio, with values censored at the initiation of dialysis. Figure 2 shows the association between the dose equivalent per milliliter
ratio and the time to death or dialysis for ARF during hospitalization, comparing
patients not taking diuretics and those with high and low dose equivalent
per milliliter ratios (log-rank χ2, P<.001).

COMMENT

Diuretics have been widely used in ARF despite little evidence of benefit.25,26 Indeed, several prospective clinical
trials have evaluated the effect of loop diuretic agents, usually at high
doses, in prevention and/or treatment of ARF.14,17,27 Most
studies15- 17 were
relatively small and confounded by cointerventions such as low-dose dopamine
hydrochloride or mannitol. Aside from augmenting urine output, few studies
have demonstrated any material benefit of diuretics in ARF, whereas other
studies have suggested potential deleterious effects.12,26- 28 For
example, Lassnigg et al12 showed that postoperative
ARF (defined as an increase in serum creatinine level of ≥0.5 mg/dL [44
µmol/L]) was more frequent in patients given furosemide (15%) compared
with dopamine (2%) or isotonic sodium chloride (0%).

In this study, 59% of patients were taking diuretics at the time of
nephrology consultation and 12% started taking diuretics after consultation.
Diuretic use at the time of consultation was significantly associated with
older age, presumed nephrotoxic (rather than ischemic or multifactorial) ARF
origin, a lower BUN level, acute respiratory failure, and a history of congestive
heart failure. After adjusting for covariates associated with the risk of
death,24 diuretic use was significantly associated
with in-hospital mortality and nonrecovery of renal function, even after adjustment
for nonrandom treatment assignment using propensity scores.

Possible explanations for the associations observed include a direct
toxic effect of diuretics or indirect effects either related or unrelated
to renal function. Providers of care in ICUs may underestimate the severity
of renal injury when urine output is sustained. Although we and others have
shown oliguria to be associated with adverse outcomes in ARF,19,24,29- 33 it
is unclear whether diuretic use modifies the effect of oliguria on mortality
or nonrecovery of renal function. We have previously shown that oliguria and
a low serum creatinine level (associated either with low creatinine generation
or dilution with extracellular volume overload) are the 2 factors most closely
related to delay in nephrology consultation among patients who have ARF on
ICU admission.34 If nonoliguria delays recognition
of ARF or recognition of the severity of ARF, then the use of diuretics might
influence ICU management, including the timing of dialysis. The relative 1-
to 2-day delay in time from consultation to initiation of dialysis in patients
taking diuretics suggests that practice patterns differ among patients taking
and not taking diuretics. If persons die from rather than with ARF, as others
and we have suggested,35- 37 delay
in initiation of dialysis (waiting for a response to diuretics) may have untoward
effects. These effects could include the worsening of respiratory, cardiovascular,
central nervous system, and immune function due to volume overload and the
effects of uremia.

In addition to the major findings linking diuretic use to mortality
and nonrecovery, we highlighted the potential importance of severity of renal
injury in determining ARF outcomes. Biopsies are rarely performed in patients
with ARF, and no reliable, valid index of ARF severity has yet been developed.
In this study, we showed that the increased risk associated with diuretic
use was largely borne by those individuals who were relatively resistant to
the agents, confirming and extending the findings previously reported by Cantarovich
and Verho38 in a multicenter French study.
In addition, we found that the degree of diuretic resistance on consultation
day 1 predicted subsequent changes in BUN and creatinine concentrations, with
the former paradoxically rising faster in more diuretic-responsive patients.
If this index (total daily furosemide dose equivalent per milliliter per day
of urine output) were validated in other settings, it might serve as a means
to risk stratify patients early in ARF. In other words, if a patient with
early ARF has low or declining urine output despite high doses of loop diuretics,
then further delay in instituting corrective therapy may not be warranted,
since the likelihood of death or the need for dialysis in the short term is
extremely high. In this way, the practice of a "diuretic challenge" need not
be abandoned but rather modified. Ultimately, identifying the optimal timing
of initiation of dialysis (or hemodiafiltration) in ARF will have to be determined
in a prospective randomized trial.

There are several important limitations to this study. Even with propensity
score adjustment, we cannot truly evaluate the effect of
diuretics, as we could in a prospective randomized trial. Although the propensity
score can adjust for confounding by indication and selection bias, we cannot
eliminate residual confounding due to unobserved factors. We had no kidney
biopsy data and no method by which direct toxic injury induced by diuretics
could be proved or refuted. Therefore, we were unable to derive any mechanistic
explanation for the findings described herein. Although this was a multicenter
study, the hospitals were all within a single region, and the results described
may not be generalizable to other regions or practice settings (eg, settings
where the availability of dialysis services may differ). These patients were
critically ill. Therefore, we cannot extrapolate the results to individuals
with less severe forms of ARF or with ARF in the absence of critical nonrenal
disease. Moreover, since all patients included in this study had a significant
increase in serum creatinine levels, we cannot infer that diuretics would
be harmful in patients very early in ARF, although there is no evidence that
they would be of benefit based on studies in ARF prevention.27

Although the data were collected mainly in the 1990s, ARF practice patterns
have not changed significantly since that time. In randomized clinical trials
(1995-1999) that tested the efficacy of other agents known to augment urine
output (eg, atrial natriuretic peptide, low-dose dopamine), 43% to 55% of
patients with ARF in the ICU were treated with diuretics, even with sustained
oliguria.28,39 In a recent survey
of the European Workgroup of Cardiothoracic Intensivists,12 11
of 38 used continuous infusions of furosemide for "renoprotection" and 34
of 38 used furosemide bolus injections when urine output decreased to less
than 0.5 mL/kg per hour. Although some nonrenal ICU therapies (eg, methods
of mechanical ventilation, frequency of pulmonary artery catheter use, choice
of antibiotics) have changed during the past several years, it is unlikely
that these changes have modified the relations among diuretic use and outcomes
in critically ill patients with ARF.

In summary, we determined that diuretic use was associated with adverse
outcomes in ARF. The increase in mortality and nonrecovery of renal function
observed may be due to a direct deleterious effect of diuretic agents, a delay
in the institution of renal support (in effect, forestalling dialysis with
volume overload or with anticipated reversal of azotemia), or other or unknown
factors. Although we cannot securely determine that diuretics are harmful,
it is highly unlikely that diuretics afford ARF patients any material benefit.
In the absence of compelling contradictory data from a randomized, blinded
clinical trial, we should discourage the widespread use of high-dose diuretics
in critically ill patients with ARF.